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Heat shock proteins are co-opted for cancer

CAMBRIDGE, Mass. (Sept. 20, 2007) A Jekyll-Hyde mechanism that both protects healthy cells and enables cancer cells could be the basis for new cancer-fighting drugs.

Scientists in the laboratory of Whitehead Member Susan Lindquist have discovered that a certain transcription factora protein that binds to specific areas of the genome and acts to switch genes on and offknown to aid in handling stresses also facilitates the survival of cancer cells.

According to the study, which appears online in Cell on Sept. 20, this transcription factor may be the basis for powerful new ways to fight cancer.

The transcription factor is the master regulator of cells protective heat-shock responsea complex and multifaceted defense system that kicks in when an organism is exposed to increased temperature, infection, toxins or other stresses. The heat-shock response is thought to have existed for more than a billion years and is found in organisms from bacteria to fruit flies to humans.

Heat-shock transcription factors turn on genes for helpful chaperone proteins that help keep proteins from going bad. If proteins form unhealthy clumps, heat-shock proteins (HSPs) pull them apart. If proteins misfold, HSPs help them refold. If the errant proteins are too far gone, HSPs ship them off to be destroyed.

Postdoctoral associate Chengkai Dai and his colleagues looked at the role of heat-shock factor 1 (HSF1), the master regulator of the heat-shock response, in enabling normal cells to turn into cancer cells.

This work provides the first direct evidence of an important role for HSF1 in helping cells to undergo a malignant transformation, says co-author Luke Whitesell, a research scientist in the Lindquist lab.

While the transcription factor does not itself cause the transformation of a normal cell into a cancer cell, it orchestrates a network of core functions in the cancer cells that govern their proliferation, survival, protein synthesis and metabolism.

In mice, an HSF1 deficiency drastically limited tumor formation induced by either a chemical carcinogen or a cancer-causing genetic mutation.

Using cells from a variety of human tumors, Dai showed that depriving the cancer cells of HSF1 strongly suppressed their ability to grow and survive. We propose that HSF1 could provide a uniquely effective target for the discovery of broadly active anticancer agents, says Lindquist.

Its increasingly apparent, Whitesell comments, that many biological mechanisms can play dual rolessometimes beneficial, sometimes not.

It makes perfect sense to us that HSF1 plays this dual role, Dai says. It has been shown that HSF1 is involved in protecting against neurodegeneration, in which brain cells die slowly over time. In cancer, the opposite is true: cancer cells dont die. Ironically, cancer cells hijack and exploit this evolutionarily conserved self-protective function of HSF1.

In fact, he says, cancer cells appear much more sensitive than normal cells to the loss of HSF1 function.

It will be interesting to see how the insights gained from studies such as this one can be applied to develop useful therapeutics, Whitesell says. The next step is to look for existing compounds that induce or inhibit the heat-shock response in cells. The challenge will be to manipulate the target for therapeutic advantage without tipping the scales too much or in the wrong places.


Contact: Eric Bender
Whitehead Institute for Biomedical Research

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